Alzheimer's research makes significant progress

November 08, 1994|By Robert Cooke | Robert Cooke,Newsday

Although it's probably too late to help former President Reagan and others showing signs of Alzheimer's disease, scientists said yesterday that the pace of research into causes and potential treatments is advancing at a breathtaking pace.

There is no cure for Alzheimer's, which afflicts about 4 million people in the United States, and what causes it is not known. But researchers are finding clues to what may be going wrong to damage memory centers in the brain, and are running experiments to see if damage to the brain can be slowed, or even blocked.

A research team in Chicago reported yesterday that putting nerve growth factor into the brain tissues of aged monkeys helps nerve cells survive and causes some to sprout new fibers that connect with other nerve cells. The finding is still very far from being a useful treatment in humans.

"This is the first demonstration of an effect of nerve growth factor upon the vulnerable neurons in an aged primate," said neuroscientist Jeffrey Kordower. "We found we were able to prevent degeneration of these cells in an aged primate."

The work, reported yesterday in the Proceedings of the National Academy of Sciences, supports earlier results in rats and young monkeys that suggest brain cells can be protected. It was the first experiment in old monkeys, between 24 and 29 years of age.

But Dr. Kordower, at the Rush Presbyterian-St. Luke's Medical Center, and other scientists said the most important tests are yet to come. They don't know if increased longevity of brain cells actually does any good, or whether it measurably improves behavior. Such tests will be expensive, difficult, time-consuming -- and are just now getting under way.

Alzheimer's disease begins, and worsens, as nerve cells in several parts of the brain, including the basal forebrain and cerebral cortex, gradually die off. Particularly vulnerable are the so-called cholinergic neurons, which make a signaling chemical called acetylcholine, which is important in memory function.

The earliest noticeable Alzheimer's symptom is memory loss, often followed by personality changes. In genetically susceptible people the illness can start in the 50s and 60s; in most of the others it strikes in the 70s and 80s. The dementia usually progresses steadily, becoming well advanced after three years.

Mr. Reagan, 83, announced he has Alzheimer's disease by releasing a handwritten note Saturday. He wrote: "I now begin the journey that will lead me into the sunset of my life." His office in Los Angeles reported a flood of sympathy messages yesterday from around the world.

At present, Alzheimer's disease is thought to be the fourth-leading cause of death in the United States, causing more than 100,000 deaths per year. The only approved drug for the disease, Tacrine, may slow progression of the disease, but the data are controversial.

In the past few years, genetic and epidemiological studies have revealed several forms of genetic susceptibility to Alzheimer's disease. A gene that causes the disorder very early in life in rare families is on chromosome 14. Another gene that makes an abnormal form of a brain protein, the amyloid precursor, is on chromosome 21. And a third susceptibility gene, for a protein called ApoE, is on chromosome 19.

Most excitement now surrounds the work of Dr. Allen Roses, at Duke University, who reports that inheriting a special combination of ApoE genes -- two copies of the ApoE4 version -- increases vulnerability to the disease eightfold. ApoE stands for apolipoprotein E.

Dr. Roses suspects that ApoE's normal job is to protect other proteins used inside the cell to transport nutrients. Inheriting two copies of the ApoE4 gene is like being dealt a bad poker hand; the ApoE protein fails to adequately protect the transport proteins. The result seems to be excess accumulation of rigid globs of amyloid, large masses of tangled fibers outside the cells and, eventually, dead nerve cells.

"This ground-breaking discovery has now mushroomed to the point where several dozen laboratories have confirmed the finding," said Zaven Khachaturian, head of Alzheimer's disease research at the National Institute of Aging, in Bethesda.

"We now can see the light at the end of the tunnel."

He explained: "We know ApoE is involved in cell repair mechanisms . . . and that having a different flavor of ApoE determines one's ability to withstand the onslaught of damage that occurs during a lifetime. This differential in repair mechanisms may account for the 20-year delay in the onset of the disease between those with ApoE4 and with ApoE2 and ApoE3."

In the work with old monkeys, Dr. Kordower and his co-workers put a gene making human nerve growth factor into connective tissue cells from hamsters. The engineered hamster cells were then encased in a porous plastic material, which was implanted into the three monkeys' brains. The plastic capsule lets growth factor leak out but prevents immune rejection of the "foreign" cells.

The capsules were still secreting nerve growth factor after one month, Dr. Kordower said. Autopsy tests showed that fewer brain cells had died in response to injury and showed "robust sprouting" of new nerve fibers.